Self-nonself discrimination is one of the cornerstones of immunology. Normally, individuals develop tolerance to self constituents during the early development of the immune system. However, the maintenance of this unresponsive state requires the persistence of antigen, a fact which implies that tolerance induction is a lifelong process. Smith, Advances in Immunology, 1:67 (1961). Indeed, the breakdown of tolerance in older individuals explains the increased incidence of autoimmunity in aging populations.
Isologous or heterologous gamma globulins have been used as tolerogenic carrier molecules (primarily IgG's). Scott, Immunol. Rev., 43:241 (1979). Although different sources of IgG's may vary in their persistence and/or mechanism of tolerance induction, by far, IgG carriers have been the most efficacious at tolerance induction in adults to haptens, nucleosides and peptides. Borel, Immunological Reviews, 50:71 (1980); and Scott, Cell Immunol., 22:311 (1976). These carriers owe their superior tolerogenicity to their persistence in vivo and the ability of epitopes chemically attached to IgG's to crosslink mIgM with B-cell Fc receptors. However, chemical crosslinking of epitopes to IgG carriers is limited by the availability of free amino groups and the uncontrolled targeting of the added determinant to different portions of the IgG.
Recombinant DNA technology can be used to genetically engineer molecules having heterologous epitopes. For example, heterologous oligopeptide epitopes of biological interest have been expressed in bacterial flagellin (Jennings et al., Protein Eng., 2:365 (1989)); hepatitis B surface antigen (Rutgers et al., Biotechnology, 6:1065 (1988)); and in the complementarity determining regions of immunoglobulins (Zanetti et al., Nature, 355:476 (1992). Some attempts have been made to test the ability of recombinant proteins to serve as antigens to immunize animals and generate immune responses to the heterologous oligopeptide. However, induction and maintenance of tolerance to oligopeptides presented to the immune system has not been demonstrated. The ability to maintain tolerance to an antigen or epitope requires persistence of the epitope in vivo.
Therefore, there is a need to develop a method of inducing stable and long lasting tolerance to an epitope. There is a need to develop a vector that can provide for persistence of the epitope in vivo so that tolerance is maintained. There is a need to develop a recombinant vector which codes for a recombinant polypeptide that has a heterologous epitope and that can be used to induce and maintain tolerance in individuals.